Starting from the 1980s, randomized trials have compared the effects of different blood pressure lowering medication on cardiovascular events. Meta-analysis of these trials did not find any substantial differences between treatment regimens and combined cardiovascular outcomes. Generally, the major benefit, including protection against stroke, was attributed to the treatment regimen offering lower BP level.
However, some data showing that in the case of primary stroke prevention, calcium channel blockers may be more effective than other groups of drugs. In the ASCOT-BPLA study, a treatment regimen based on amlodipine was more effective in stroke reduction than treatment based on atenolol. However, there was a slightly lower blood pressure achieved in the amlodipine arm than in the atenolol arm, and it may be responsible for observed differences in stroke risk [91
]. The reduced risk of stroke in patients treated with a calcium channel antagonist as compared with other classes of BP lowering medications did not reach statistical significance in other trials [100
Results of the ASCOT-BPLA trial opened a debate on the role of beta-blockers in the treatment of uncomplicated hypertension. Some group of experts recommended avoiding use of beta-blockers as first line treatment due to their lower protection against stroke [106
]. Meta-analysis by Law et al. [100
••] included all identified randomized trials of BP lowering drugs in which coronary events or stroke were recorded. The relative risk estimates for stroke in the drug comparison trials were close to 1.0, with two exceptions: greater preventive effect of calcium channel blockers than other drugs (relative risk 0.91, 95 % confidence interval 0.84 - 0.98; p
0.01), and a lesser effect of β blockers (relative risk 1.18, 1.03 - 1.36; p
0.02). The differences remained significant after adjustment for the small difference in blood pressure reduction between the groups. The observed lesser effect of β blockers, however, was based on trials that directly compared calcium channel blockers with β blockers. Exclusion of the results of these trials from meta-analysis weakened the evidence favoring a disadvantage of β blockers over the three other classes (relative risk 1.11, 0.86 - 1.44; p
0.40) but had little effect on the strength of evidence favoring an advantage of calcium channel blockers over the three other classes of drug (relative risk 0.93, 0.86 to 1.01; p
0.07). The results of comparisons of different classes of antihypertensive drugs were similar in primary and secondary prevention of stroke.
Beta-blockers and calcium channel antagonists differ in their influence on central BP measured in the aorta. The Conduit Artery Function Evaluation (CAFÉ) substudy of ASCOT BPLA showed greater reduction of central SBP as compared to brachial BP in patients in the amlodipine arm than in subjects on atenolol-based therapy [107
]. For a similar effect on brachial BP, amlodipine lowered central SBP by an additional 4.3 mm Hg as compared to atenolol. The influence on central aortic BP might explain the results of the Nordic Diltiazem (NORDIL) trial where, despite lower systolic BP by 3 mm Hg, the number of fatal and nonfatal strokes was significantly higher on beta-blocker than during administration of calcium channel blocker (7.9 vs 6.4 events per 1000 patient-years; p
]. Ding et al., performed a meta-analysis including trials that compared beta-blockers with other classes of anti-hypertensive agents in their effect on stroke and central hemodynamics [109
]. In nine trials, beta-blockers reduced central aortic pressure (estimated as an Augmentation Index, AI) to less extent than other classes of drugs. The difference in central systolic BP could be largely explained by the heart-rate slowing effect of beta-blockers. In a subsequent meta-regression of these trials , the base-line adjusted change in heart rate by ten beats per minute was associated with a significant increase of AI by 7 %. In outcome trials, odds ratio for stroke was 1.23, which corresponds to the difference in central SBP derived from the above meta-regression analysis.
Calcium channel blockers lower BP acting on resistance arterioles and in a small, but interesting study on stroke outcome, survivors of acute stroke had a lower systemic vascular resistance [110
Differences between angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on the risk of stroke were investigated in the meta-analysis including trials in subjects with high cardiovascular risk (ONTARGET), heart failure (ELITE), post-MI (OPTIMAAL, VALIANT) or diabetic nephropathy (DETAIL). Although both groups of drugs reduced BP to the same extent, and there was no difference in the risk of cardiovascular mortality and MI, the risk of stroke was slightly lower with ARBs than ACE inhibitors (odds ratio 0.92; 95 % confidence interval 0.85-0.99; P
Major clinical trials with different classes of BP lowering drugs in hypertensive populations without previous history of cerebrovascular events (less 5 % of stroke victims at the baseline) are listed in Table .
Major clinical trials with different classes of BP lowering drugs in hypertensive population without previous history of cerebrovascular events (less 5 % of stroke victims at the baseline)
Visit-to-visit BP variability is a predictor for future stroke and in the ASCOT BPLA trial this parameter was greater in the atenolol than in the amlodipine group [91
]. Webb et al., using data from 389 trials analyzed the effect of different classes of antihypertensive drugs on BPV [92
••]. Compared with other drugs, interindividual variation in SBP was reduced by calcium-channel blockers and non-loop diuretic drugs, and increased by ACE inhibitors, ARBs and beta-blockers. Compared with placebo only, interindividual variation in SBP was reduced the most by calcium-channel blockers. In another study, they analyzed within-individual visit-to-visit variability using data from two trials: ASCOT BPLA comparing atenolol and amlodipine-based regimens and the Medical Research Council (MRC) comparing atenolol-based with diuretic-based BP lowering therapy [112
]. In patients during the MRC study, BPV increased on beta-blocker treatment comparing to placebo and diuretic. Subsequent temporal trends in variability in blood pressure during follow up in the atenolol group correlated with trends in stroke risk. In ASCOT BPLA, variability decreased over time in the amlodipine group and increased in the atenolol group. The authors conclude that the opposite effects of calcium-channel blockers and beta-blockers on variability of blood pressure account for the disparity in observed effects on risk of stroke and expected effects based on mean blood pressure. The effects of calcium channel blockers on BPV persisted when they were used in combination with other agents [113
However, in the above mentioned studies atenolol was given once daily despite its relatively short half-life of 6-7 hours. Limited duration of BP lowering effect of atenolol could cause episodic hypertension and increased BPV. Comparison of different beta-blockers showed that beta1-selective is associated with lower BPV than are the non-selective beta-blockers. Among vasodilating beta-blockers, carvedilol (non-selective) increases BPV, while nebivolol (selective) does not affect BPV [114
The reduction in BPV was also associated with the frequency of headaches. In a systematic review of randomized trials it was demonstrated that antihypertensive treatment reduced the incidence of headache compared to placebo, but there were significant differences in the magnitude of the effect, independent of reduction in systolic BP [115
]. Beta-blockers reduced headache more than other classes and calcium channel blockers did not reduce headache compared to placebo and increased it compared to other drug classes. The mechanism underlying these findings and their clinical significance is unknown.
According to the studies on BPV and stroke prevention, an ideal antihypertensive drug should reduce both mean blood pressure and variability.